How Not to Miss Autoinflammatory Diseases Masquerading As Urticaria

REVIEW ARTICLE How not to miss autoinﬂammatory diseases masquerading as urticaria K. Krause1,2, C. E. Grattan3, C. Bindslev-Jensen4, M. Gattorno5, T. Kallinich1,6, H. D. de Koning7,8, H. J. Lachmann9, D. Lipsker10, A. A. Navarini11, A. Simon7, C. Traidl-Hoffmann12,13 & M. Maurer1,2

1Autoinflammation Reference Center Charite´ , Charite´ -Universita¨tsmedizin Berlin, Berlin, Germany; 2Department of Dermatology and Allergy, Charite´-Universita¨tsmedizin Berlin, Berlin, Germany; 3St John’s Institute of Dermatology, St Thomas’ Hospital, London, UK; 4Department of Dermatology and Allergy Center, Odense University Hospital, Odense, Denmark; 5UO Pediatria II, G. Gaslini Institute, Genova, Italy; 6Pediatric Pneumology and Immunology, Charite´ -Universita¨tsmedizin Berlin, Berlin, Germany; 7Department of General Internal Medicine, Nijmegen Institute for Infection, Inflammation and Immunology (N4i), Centre for Immunodeficiency and Autoinflammation (NCIA), Radboud University Nijmegen Medical Centre; 8Department of Dermatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; 9National Amyloidosis Centre, University College London Medical School, London, UK; 10Faculte´ de Me´ decine, Hoˆ pitaux universitaires de Strasbourg, Universite´ de Strasbourg et Clinique Dermatologique, Strasbourg, France; 11Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland; 12Department of Dermatology and Allergy Biederstein, Technische Universita¨t, Munich, Germany; 13ZAUM – Center for Allergy and Environment, Technische Universita¨t Munich, Helmholtz Center Munich, Munich, Germany

To cite this article: Krause K, Grattan CE, Bindslev-Jensen C, Gattorno M, Kallinich T, de Koning HD, Lachmann HJ, Lipsker D, Navarini AA, Simon A, Traidl-Hoffmann C, Maurer M. How not to miss autoinﬂammatory diseases masquerading as urticaria. Allergy 2012; 67: 1465–1474.

Keywords Abstract autoinflammation; cryopyrin-associated Urticarial skin reactions are one of the most frequent problems seen by allergists periodic syndrome; interleukin-1; Schnitzler’s syndrome; urticaria. and clinical immunologists in daily practice. The most common reason for recurrent wheals is spontaneous urticaria. There are, however, several less common Correspondence diseases that present with urticarial rash, such as urticarial vasculitis and autoin- Marcus Maurer, Department of Dermatology flammatory disorders. The latter include cryopyrin-associated periodic syndrome and Allergy, Charite´ – Universita¨tsmedizin and Schnitzler’s syndrome, both rare and disabling conditions mediated by Berlin, Charite´ platz 1, D-10117 Berlin, increased interleukin-1 secretion. Apart from the urticarial rash, patients are suf- Germany. fering from a variety of systemic symptoms including recurrent fever attacks, Tel.: +49 30 450 518 043 arthralgia or arthritis and fatigue. Autoinflammatory diseases are often associated Fax: +49 30 450 518 972 with a diagnostic delay of many years and do not respond to antihistamines and E-mail: [email protected] other treatments of urticaria. Also, the chronic inflammation may lead to long- Accepted for publication 15 August 2012 term complications such as amyloidosis. It is therefore important not to miss these diseases when diagnosing and treating patients with chronic recurrent urti- DOI:10.1111/all.12030 carial rash. Here, we present clinical clues and tips that can help to identify autoinflammatory disorders in patients presenting with chronic urticarial rash Edited by: Hans-Uwe Simon and discuss their clinical picture and management.

Abbreviations Urticarial rash: a diagnostic conundrum AOSD, Adult-onset Still’s disease; CAPS, Cryopyrin-associated Urticarial rashes are among the most frequent problems seen periodic syndrome; CRP, C-reactive protein; CSU, Chronic by allergists and clinical immunologists in daily practice. spontaneous urticaria; ESR, Erythrocyte sedimentation rate; FCAS, Patients present with multiple wheal-and-flare-type skin Familial cold autoinflammatory syndrome; FMF, Familial lesions that are usually itchy. Acute urticaria is characterized Mediterranean fever; HIDS, Hyper-IgD and periodic fever syndrome; MAS, Macrophage activation syndrome; MKD, by transient recurrent wheals and/or angioedema for up to Mevalonate kinase deficiency; MWS, Muckle–Wells syndrome; 6 weeks. It may be associated with acute upper respiratory NOMID, Neonatal onset multisystem inflammatory disease; tract viral infections or intolerance reactions to foods or PFAPA, Periodic fever, aphthous stomatitis, pharyngitis and drugs (1). In most cases, symptoms rapidly cease to occur adenitis; SAA, Serum amyloid A; SchS, Schnitzler’s syndrome; after a couple of days or weeks, and the causes of acute urti- SLE, Systemic lupus erythematosus; soJIA, Systemic-onset caria are usually not a reason for ongoing concern. juvenile idiopathic arthritis; TNF, Tumour necrosis factor; TRAPS, Chronic urticaria is much less common than acute urticaria TNF-receptor-associated periodic syndrome. but still a frequent condition. In patients with recurrent

Allergy 67 (2012) 1465–1474 © 2012 John Wiley & Sons A/S 1465 Chronic urticarial rash: signs for autoinflammation Krause et al. wheals, chronic spontaneous urticaria (CSU) is the most complications, impaired quality of life and long-term, often common underlying disease (Table 1). Chronic spontaneous poorly effective, immunosuppressive therapies including sys- urticaria, that is, recurrent spontaneous wheals, angioedema temic glucocorticoids and others which carry their own seri- or both occurring on a regular basis for more than 6 weeks, ous side effects. Despite some recent important advances, the has a point prevalence of 0.5–1% in the European popula- diagnosis and treatment of autoinflammatory syndromes tion (2). It is often associated with intolerance reactions to remain challenging. Skin manifestations such as urticarial food and drugs, chronic infections and autoreactivity (i.e. rash are among the earliest and most prominent symptoms in inflammatory skin reactions after intracutaneous injection of these disorders. In fact, urticarial eruptions are prototypic autologous serum) or functional autoantibodies (1). In addi- skin lesions of autoinflammatory conditions and can help to tion, there are a number of inducible forms of chronic urti- identify these diseases in their early stages (Table 2). caria (e.g. dermographic, cold-induced, solar, cholinergic urticaria), which are elicited by physical or other stimuli such Cryopyrin-associated periodic syndrome as water, UV light or an increase in body temperature. The underlying mechanisms of inducible chronic urticarias are Urticarial rash, or in some cases maculo-papular rash, occurs largely unknown. As in spontaneous urticaria, the first-line in almost all patients with CAPS. Further symptoms include symptomatic treatment of choice is the use of nonsedating recurrent fever attacks, arthralgia or arthritis, eye inflamma- antihistamines (3). Importantly there are several much less tion, fatigue and headaches. Cryopyrin-associated periodic common diseases all of them autoinflammatory disorders, syndrome, also called cryopyrinopathies, used to be classified that mimick urticaria (4) (Table 1). as three distinct entities and was previously referred to as familial cold autoinflammatory syndrome (FCAS), Muckle– Wells syndrome (MWS) or neonatal onset multisystem Autoinflammatory diseases inflammatory disease (NOMID). It is now clear that CAPS In contrast to autoimmune diseases, which are mediated by covers a continuum of disease severity with considerable T and B cells and other key players of adaptive immunity, overlap in clinical symptoms and a lack of clear genotype/ autoinflammatory diseases are disorders of the innate phenotype correlation (8) (Table 2). With about 1000 known immune system. The best understood autoinflammatory dis- patients worldwide, CAPS represents an orphan disease. It is eases are the hereditary periodic fever syndromes, which caused by autosomal dominant mutations in the NLRP3 include cryopyrin-associated periodic syndrome (CAPS), gene that encodes cryopyrin, a key component of an intracel- familial Mediterranean fever (FMF), hyper-IgD syndrome lular multiprotein complex, named the NLRP3 inflamma- (HIDS) and TNF-receptor-associated periodic syndrome some, which regulates the processing of interleukin-1b (TRAPS). They are characterized by episodic fever and (IL-1b), a potent pro-inflammatory cytokine (9). The sponta- chronic inflammation of the skin, joints and various other neous secretion of IL-1b from macrophages (10) and skin organs. Amyloid A amyloidosis as a result of the chronic mast cells of patients with CAPS (11) as well as the dramatic inflammation is the most serious long-term complication of response to treatment with IL-1b neutralizing drugs (12–14) these diseases (5). Patients often suffer from a markedly indicates that IL-1b plays a central role in the pathogenesis impaired quality of life, and the number of missed school of CAPS. Cryopyrin-associated periodic syndrome is diag- and working days is high (6, 7). nosed on the basis of the clinical presentation, family history Autoinflammatory disorders are very rare entities, and and laboratory work-up including mutation analysis. The limited disease awareness even among specialist physicians treatment with IL-1b neutralizing drugs has been shown to often results in a diagnostic delay of many years or even dec- be effective and well-tolerated in all three subgroups of ades. Delay in diagnosis may lead to irreversible long-term CAPS (12–17).

Table 1 Underlying mechanisms and causes of chronic urticarial rash

Mast cell mediator–mediated Interleukin-1-mediated*

Chronic spontaneous urticaria (CSU) Cryopyrin-associated periodic syndrome (CAPS) CSU due to autoreactivity CSU due to functional autoantibodies Schnitzler’s syndrome (SchS) CSU due to infection CSU due to intolerance Other autoinflammatory disorders: CSU due to unidentified causes NLRP12-associated cold-induced autoinflammatory syndrome (FCAS2) Inducible urticarias Systemic-onset juvenile idiopathic arthritis (soJIA) Adult-onset Still’s disease (AOSD) Mevalonate kinase deficiency (MKD) TNF-receptor-associated periodic syndrome (TRAPS)

*Interleukin-1 may also be, at least in part, mast cell-derived.

67 CAPS MKD

21)1465–1474 (2012) NLRP12- Schnitzler’s associated Mevalonic FCAS MWS NOMID syndrome FCAS soJIA AOSD HIDS aciduria TRAPS

Skin Urticarial Urticarial Maculo- Urticarial rash Urticarial rash Fleeting Fleeting Morbilliform rash > Migratory manifestation rash rash papular salmon- salmon- urticarial rash painful

© exanthema coloured coloured erythemas 02Jh ie osA/S Sons & Wiley John 2012 >Urticarial macular rash macular rash >urticarial rash >urticarial rash >urticarial rash rash Gene/ NLRP3/ NLRP3/ NLRP3/ Complex NLRP12/ Complex Complex MVK/Autosomal TNFRSF1A/ Inheritance Autosomal Autosomal Sporadic Autosomal recessive Autosomal pattern dominant dominant or autosomal dominant dominant dominant Age of First 6 Infancy to Neonatal Ca. 50 years Infancy to <16 years 16 years Infancy Early disease months adolescence or early adolescence childhood onset of life infancy Distinctive Symptoms Sensorineural Aseptic Monoclonal Symptoms Serum Ferritin/ Serum Ferritin/ Aphthous ulcers Periorbital features mainly hearing loss meningitis gammopathy (exclusively) Exclusion of Exclusion of Lymphadenopathy oedema triggered Arthropathy triggered other diseases other diseases Serum IgD ↑ MVK↓ Abdominal by cold by cold pain Flare pattern <24 h flares 24–48 h Continuous <24–48 h flares 2–10 days Strongly 7–14 days 3–7 days flares 7–21 days flares symptoms Continuous flares varying, flares flares Continuous with flares symptoms monophasic, symptoms with flares polyphasic with flares and continuos courses possible Amyloidosis Low 25–33% Low Low Not known Low Low 14–25% of autoinflammation for signs rash: urticarial Chronic risk patients Complications Sensorineural Chronic Lymphoproliferative MAS MAS Exacerbation Cerebellar Fasciitis deafness meningitis disorder Devastating Devastating after ataxia in 40% with arthritis arthritis immunization Mental CNS retardation damage Haematological Severe abnormalities infections Treatment IL-1 IL-1 IL-1 IL-1 blockade Glucocorticoids Glucocorticoids Glucocorticoids Glucocorticoids Glucocorticoids blockade blockade blockade IL-6 blockade IL-1 blockade IL-1 blockade IL-1 blockade TNF blockade IL-1 blockade IL-6 blockade IL-6 blockade IL-1 blockade IL-6 blockade

CAPS, Cryopyrin-associated periodic syndrome; AOSD, Adult-onset Still’s disease; soJIA, Systemic-onset juvenile idiopathic arthritis; HIDS, Hyper-IgD and periodic fever syndrome; MWS; Muckle–Wells syndrome; NOMID, Neonatal onset multisystem inﬂammatory disease; AOSD, Adult-onset Still’s disease. 1467 Chronic urticarial rash: signs for autoinﬂammation Krause et al.

Schnitzler’s syndrome autosomal dominant inherited disorder resembles a mild form of CAPS. Thus, symptoms in most patients are limited Schnitzler’s syndrome (SchS) is characterized by recurrent to cold-induced urticarial rashes, arthralgia and myalgia (30) urticarial skin lesions (Fig. 1) and a monoclonal gammopa- (Table 2). thy (IgM or IgG class) in combination with signs and symptoms of systemic inflammation (18). The frequency of urticarial rashes varies considerably among patients. Most Adult-onset Still’s disease patients report daily symptoms, but some experience urticar- The main diagnostic criteria for Adult-onset Still’s disease ial rashes only a few times a year. Other symptoms in SchS (AOSD) include recurrent fever attacks >39°C for a mini- include recurrent fever attacks, bone and muscle pain, mum of 1 week, pharyngitis, arthralgias, a neutrophilic leu- arthralgia or arthritis, and lymphadenopathy (19) (Table 2). kocytosis as well as a salmon-coloured maculopapular SchS is a very rare disease with <150 reported cases (20). The exanthema, which typically appears with the onset of fever in first symptoms usually start at the age of 50, and it seems to the evenings and decreases in the mornings (31) (Table 2). In be an acquired disorder. Spontaneous remissions have only addition, urticarial rashes and persistent pruritic papules and very rarely been reported (21, 22). About 15% of patients plaques have been reported in AOSD (32). Laboratory find- eventually develop a lymphoproliferative disorder, most often ings indicative of AOSD include elevated serum ferritin levels Waldenstro¨ m’s macroglobulinemia (20). The pathogenesis of with a reduced glycosylated ferritin fraction (33, 34). A diag- SchS is unknown but widely assumed to be inflammasome- nosis of AOSD requires exclusion of infectious diseases, and IL-1b-mediated, similar to that of CAPS (23). malignancies and other rheumatologic diseases. Owing to the limited awareness and rarity of the disease, many cases of SchS take years and even decades to be diagnosed. Consequently, patients usually receive multiple inade- Systemic-onset juvenile idiopathic arthritis (soJIA, syn M. quate and useless therapies before being treated effectively. Still’s disease) At present, there is no licensed standard therapy available Systemic-onset juvenile idiopathic arthritis is characterized by for the treatment of SchS. Case series, however, report suc- intermittent high-spiking fever, a maculopapular or urticarial cessful treatment of SchS with anti-IL-1 therapies resulting in exanthema (Fig. 2) and developing (poly-) arthritis in chil- complete or nearly complete remission of symptoms in dren <16 years of age (35). The clinical presentation of symp- almost all cases (24–28). toms in soJIA is similar to that seen in AOSD, besides that the occurrence of arthritis is a mandatory criterion (Table 2). The absence of autoantibodies or human leucocyte antigen NLRP12-associated cold-induced autoinflammatory syndrome associations as well as the favourable response to IL-1 (36– (FCAS2) 38) or IL-6 blocking (39) agents in treatment-resistant Recently, single cases of NLRP3 mutation-negative, familial courses supports the hypothesis that soJIA is rather a poly- cold-induced rashes have been linked to mutations of the genic autoinflammatory disease than autoimmune disorder NLRP12 gene (29, 30). The clinical phenotype of this rare (35, 40).

Figure 1 Urticarial exanthema in a patient with Schnitzler’s syn- Figure 2 Fleeting salmon-coloured maculo-papular exanthema in a drome (SchS). patient with systemic-onset juvenile idiopathic arthritis (soJIA).

diarrhoea, arthralgia, myalgia, CNS involvement, lymphade- Mevalonate kinase deficiency (MKD)/Hyper-IgD and periodic nopathy or arthritis, and fever (Table 3). fever syndrome It should be noted that these may be very frequent symp- Mevalonate kinase deficiency includes HIDS (one of the four toms, which when presented separately usually do not raise classic monogenic autoinflammatory diseases) and the clini- suspicion of an autoinflammatory disorder. However, a com- cally more severe mevalonic aciduria. Both are caused by bination of symptoms (e.g. urticarial rash, recurrent fever of mutations in the gene coding for mevalonate kinase. Patients unknown origin and arthralgia) in addition to further hints with HIDS present with recurrent fever, abdominal pain, including a positive family history or laboratory abnormali- diarrhoea, aphthous ulcers and morbilliform exanthema ties (i.e. elevated inflammation markers) makes the diagnosis rather than urticarial lesions (Fig. 3). In addition, mevalonic of autoinflammatory disease much more likely. aciduria is associated with cerebellar ataxia, mental retardation, haematologic abnormalities and early death (41) How to distinguish isolated chronic urticaria from (Table 2). Typically, IgD levels are highly elevated in MKD autoinflammatory diseases by looking at skin lesions patients. and other symptoms The urticarial rash in patients with autoinflammatory syn- TNF-receptor-associated periodic syndrome dromes may be, at first sight, indistinguishable from that of TNF-receptor-associated periodic syndrome is another mono- urticaria patients. However, a close clinical look, a detailed genic autoinflammatory disease and caused by mutations in patient history, the assessment of treatment responses, labo- the gene encoding the TNF-receptor superfamily 1A. Clinical ratory findings and skin histopathology can provide valuable symptoms include recurrent fever attacks, abdominal pain, hints that can help to discriminate urticaria from autoinflam- arthralgia and annular wandering erythema with underlying matory disorders (Table 4). The urticarial rash in patients myalgia or, less frequently, urticarial plaques (Fig. 4). Also, with autoinflammatory syndromes has a broader spectrum of periorbital oedema is often present in patients with TRAPS lesions than urticaria, namely flat wheals that may, at first (42) (Table 2). sight, resemble erythematous patches but also more solid and stable lesions (Fig. 5). Also, the urticarial rash in autoinflammation patients is rather symmetrically distributed on the Clinical signs and symptoms other than urticarial rash trunk and/or extremities, usually sparing the head. Children, that may point to autoinflammatory disease however, may present a more generalized urticarial rash, less In CAPS, for example, urticarial rash is often the earliest frequently affecting even the face. In contrast, isolated and one of the most prominent symptoms. But autoinflam- chronic urticaria is characterized by typical itchy wheal-and- matory diseases and allergic or autoimmune disorders share flare-type skin reactions that are asymmetrically distributed many other clinical features. The list of clinical signs and and may occur anywhere on the body. The duration of single symptoms frequently presented to allergists and clinical immunologists that could also be associated with autoinflammatory disease includes inflammation of the anterior eye or uveitis resulting in eye redness and pain, periorbital oedema, serositis, stomatitis (aphthae), pustules and ulcers, meningeal inflammation causing headache, abdominal pain and

Figure 3 Erythematous plaques on the dorsal hand and forearm of Figure 4 Erythematous patches in a patient with TNF-receptor- a patient with hyper-IgD syndrome. associated periodic syndrome.

Allergy 67 (2012) 1465–1474 © 2012 John Wiley & Sons A/S 1469 1470 Table 3 Clinical signs and symptoms of selected autoinﬂammatory diseases and possible differential diagnoses autoinﬂammation for signs rash: urticarial Chronic

Autoinﬂammatory disorder

Clinical signs and symptoms CAPS Schnitzler’s syndrome NLRP12-associated FCAS soJIA AOSD MKD TRAPS Differential diagnosis

Chronic urticarial rash X X X X X X X Urticaria (spontaneous or induced, e.g. cold contact urticaria) Urticarial vasculitis

Eye redness and pain X X Allergic conjunctivitis Uveitis (autoimmune, infectious)

Periorbital oedema X Angioedema Allergic contact dermatitis

Serositis X Autoimmune connective tissue disorder Stomatitis, aphthae X Allergy Autoimmune disorder Infection

Abdominal pain, diarrhoea X X Food allergy Inﬂammatory bowel disease

Proteinuria X X X Autoimmune connective tissue disorder

Lymphadenopathy X X X X X X X Infection Malignancy Autoimmune connective tissue disorder

Myalgia X X X X Infection Autoimmune connective tissue disorder Allergy Arthralgia/arthritis X X X X X X X Rheumatoid arthritis JIA 67 Reactive arthritis 21)1465–1474 (2012) Autoimmune connective tissue disorder

Headache and other CNS symptoms X X X Migraine

02Jh ie osA/S Sons & Wiley John 2012 Immunodeﬁciency Autoimmune connective tissue disorder

The clinical signs and symptoms represent a selection of common features and are found in other nonurticarial autoinﬂammatory diseases such as familial Mediterranean fever (FMF), periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome (PFAPA), Behcet’s disease and others as well. ruee al. et Krause Krause et al. Chronic urticarial rash: signs for autoinﬂammation

Table 4 Distinguishing criteria of chronic urticaria and autoinﬂammatory syndromes

Characteristics of urticarial rash Chronic urticaria Autoinﬂammatory syndrome

Appearance Papular wheals Flatter wheals, erythematous patches Wheal-and-flare reaction but also more solid and stable lesions No wheal with surrounding flare Localization Asymmetrical distribution common Rather symmetrical distribution Duration of single lesion Transient (minutes or few hours) Hours, up to 24 h Pruritus Severe May be absent, rather burning or painful Angioedema Often associated Rare Skin histopathology Dermal oedema; partly sparse No significant dermal oedema; dense inflammatory infiltrate of perivascular neutrophil-rich perivascular and interstitial eosinophils, neutrophils and lymphocytes infiltrates, but can also be rather nonspecific Start of symptoms All ages Childhood (hereditary fever syndromes) Adulthood (acquired complex disorders) Disease duration Few years Usually life-long Response to antihistamines Moderate – good Missing Dose dependent Systemic symptoms None Recurrent fever, fatigue, arthralgia and others Inflammation markers Within normal range (Continuously) elevated Family history Negative Often positive

to hours) depending on the severity of the illness (4). Severe A pruritus represents the most bothersome symptom for many patients with chronic urticaria (43). In autoinflammatory syndromes, pruritus may be absent (20) and is rarely more than minimally symptomatic, or skin lesions are described as elicit- ing a burning sensation. In addition, many patients with chronic urticaria frequently show angioedema, which is a rare finding in autoinflammatory disease (20). Skin histopathology in urticaria predominantly shows dermal oedema. Inflamma- tory infiltrates, if any, are limited to sparse perivascular eosinophils, neutrophils and lymphocytes. In many cases of autoinflammatory disease, dense neutrophil-rich perivascular and interstitial infiltrates are seen in lesional skin (44). Systemic symptoms (i.e. fever, malaise and joint involvement) and repeatedly elevated inflammation markers such as B C-reactive protein (CRP), serum amyloid A (SAA), erythrocyte sedimentation rate (ESR) and neutrophilic leukocytosis are characteristic for autoinflammatory disorders but not for chronic urticaria. Urticaria may occur at any age, and symptoms can reoccur for several years (43). In autoinflammatory diseases, first symptoms typically appear after birth or in childhood as in CAPS, or later in life as in SchS, which starts at the age of 50 on average. Finally, autoinflammatory disorders do not respond to ‘classical’ urticaria treatments such as antihistamines or combinations of antihistamines and H2 blockers and/or leukotriene antagonists. Response to glucocorticoids is variable in different autoinflammatory disorders. Cryopyrin-associated periodic syndrome and Schnitzler’s syndrome, but not isolated chronic urticaria, respond poorly (or Figure 5 (A) Oedematous skin-coloured wheals with surrounding not at all) to glucocorticoids except at high doses of the erythema in a patient with chronic spontaneous urticaria (CSU). (B) order of a mg per kg (45). In HIDS, TRAPS, AOSD and Erythematous flat wheals in a patient with cryopyrin-associated soJIA however, oral glucocorticoids can be quite effective periodic syndrome (CAPS). (7, 34, 40, 46). Suspicion of autoinflammatory disease should prompt lesions, on average, is longer in autoinflammatory diseases appropriate diagnostic measures to rule out or confirm (hours up to 24 h) as compared to chronic urticaria (minutes CAPS, SchS or another autoinflammatory condition.

Table 5 Characteristics of cold-induced urticarial disorders

Characteristics Cold contact urticaria Systemic cold urticaria FCAS (NLRP3- and NLRP12-associated)

Localization Limited to cold-exposed area Generalized rash Generalized rash Disease trigger Cold contact (solid, liquid and air) Cold humid air, change in Cold humid air, change in temperature temperature Ice cube test Wheal-and-ﬂare reaction within Negative Negative minutes Systemic cold Generalized rash, angioedema Generalized rash within minutes, Generalized rash, fever, malaise, provocation and risk of anaphylaxis within angioedema and anaphylaxis arthralgia within 1–2h minutes possible

negative test result (no wheal-and-flare reaction 15 min after How to diagnose autoinflammatory syndromes provocation) rules out ‘classical’ cold contact urticaria and The laboratory work-up for diagnosing autoinflammatory points to atypical cold urticaria including idiopathic and syndromes should include basic inflammation markers (CRP, familial forms or cold-induced autoinflammatory disorders ESR), a differential blood count to screen for neutrophilia (53–55) (Table 5). Atypical idiopathic cold urticaria is not (neutrophils are often elevated in autoinflammatory disorders associated with systemic symptoms and develops within min- and during treatment with glucocorticoids), antinuclear anti- utes. Also, in patients with CAPS, a transient rash may be bodies to rule out autoimmune diseases and urinalysis to seen within minutes after exposure to cool temperatures. screen for proteinuria which raises the possibility of second- However, a genuine cold-triggered CAPS attack with sys- ary AA renal amyloidosis. Although not routinely available temic symptoms including fever and malaise develops not in all countries, SAA should be included as an important before hours after cold provocation (56). In patients with a inflammation marker and screening parameter for amyloido- negative ice cube test result and no history of cold-induced sis in autoinflammatory diseases. Serum amyloid A levels are anaphylaxis, a cold room provocation may be performed to elevated during disease attacks and correlate well with other distinguish atypical cold urticaria from FCAS. acute phase proteins, namely CRP and ESR (47). Persistent high SAA levels are also associated with an increased risk of Conclusion amyloidosis (48). For the detection of subclinical inflammation, the phagocyte-specific proteins S100A8/9 and S100A12 Autoinflammatory syndromes are rare and severely debilitat- have been proposed as highly sensitive biomarkers in autoin- ing chronic diseases with limited awareness. Thus, they are flammatory syndromes (47, 49). However, these are currently underdiagnosed and often recognized with a diagnostic delay limited to specialist centres. If the patient’s history, clinical of many years or even decades. Early diagnosis is of great and laboratory findings are highly suspicious of autoinflam- importance to enable effective treatment and to prevent long- matory disease such as CAPS, a selected gene mutation anal- term complications such as amyloidosis. Urticarial rash is ysis may confirm the diagnosis of hereditary periodic fever often the earliest and one of the most common and promi- syndrome. However, it should be noted that mutational anal- nent symptoms in autoinflammatory disorders. Therefore, yses are only performed by specialist centres, are usually allergists and clinical immunologists should consider them as expensive and may be negative in up to 40 to >50% of au- a potential differential diagnosis of chronic spontaneous urti- toinflammatory disorders with typical clinical symptoms (50, caria. Thinking of autoinflammatory conditions and their 51). To increase the probability of positive results from clinical profiles is the most important step in detecting these genetic testing, the use of a clinical diagnostic score, which diseases, which are readily diagnosed and treated. has recently been validated, may be helpful (52). In patients with adult-onset urticarial rash, systemic symptoms and ele- Acknowledgments vated inflammation markers, a simple immune electrophore- sis test is recommended to screen for paraproteins indicative None. of SchS. To establish a definitive diagnosis of SchS, the use of recently updated diagnostic criteria is recommended (21). Author contributions Special attention should be paid to cold-induced urticarial rashes. In cold contact urticaria as well as in FCAS1 and This manuscript is the outcome of an EAACI task force on FCAS2, cold exposure is the only or major disease-triggering autoinflammatory syndromes. Following a consensus meeting factor (Table 5). Without a detailed history and diagnostic with all co-authors in January 2011, K. Krause and M. testing, cold-induced autoinflammatory disorders may be Maurer prepared a first draft version of the manuscript. This overlooked. As a first step, a simple cold provocation test first draft was then circulated to all co-authors and revised with a melting ice cube applied on the volar forearm in a according to their corrections, comments and suggestions. All thin polythene bag for 5 min is recommended (53). A authors then again reviewed, completed or changed the

1472 Allergy 67 (2012) 1465–1474 © 2012 John Wiley & Sons A/S Krause et al. Chronic urticarial rash: signs for autoinflammation manuscript and sent it back to the first authors. After a prefi- Conflict of interest nal version was composed out of all of the changes, and a final review and approval was obtained from all contributing K. Krause, C. E. Grattan, C. Bindslev-Jensen, T. Kallinich, authors, the final version of the manuscript was submitted. H. D. de Koning, H. J. Lachmann, D. Lipsker, A. A. Nava- K. Krause and M. Maurer: substantial contributions to (1) rini, A. Simon, C. Traidl-Hoffmann declared that they have conception of manuscript, (2) drafting the article and (3) final no conflict of interest. M. Gattorno: Consultancy fees and approval of the version to be published. C.E. Grattan, C. honoraria for meeting presentations from Novartis and SOBI Bindslev-Jensen, M. Gattorno, T. Kallinich, H.D. de Koning, Biovitrum. M. Maurer: Marcus Maurer is or recently was a H.J. Lachmann, D. Lipsker, A.A. Navarini, A. Simon and Speaker and/or Advisor for Almirall Hermal, Essex Pharma, C. Traidl-Hoffmann: substantial contributions to (1) revising Genentech, Merckle Recordati, Novartis, Sanofi Aventis, the article critically for important intellectual content and (2) Schering-Plough, Merck, MSD, UCB and Uriach. final approval of the version to be published.

References 1. Zuberbier T, Asero R, Bindslev-Jensen C, plex triggering innate immunity. Curr Opin 17. Goldbach-Mansky R, Shroff SD, Wilson M, Walter Canonica G, Church MK, Gimenez- Immunol 2007;19:615–622. Snyder C, Plehn S, Barham B et al. A pilot Arnau A et al. EAACI/GA(2)LEN/EDF/ 10. Agostini L, Martinon F, Burns K, McDer- study to evaluate the safety and efficacy of WAO guideline: definition, classification and mott MF, Hawkins PN, Tschopp J. NALP3 the long-acting interleukin-1 inhibitor rilona- diagnosis of urticaria. Allergy 2009;64:1417– forms an IL-1beta-processing inflammasome cept (interleukin-1 Trap) in patients with 1426. with increased activity in Muckle-Wells au- familial cold autoinflammatory syndrome. 2. Baiardini I, Bousquet PJ, Brzoza Z, Cano- toinflammatory disorder. Immunity Arthritis Rheum 2008;58:2432–2442. nica GW, Compalati E, Fiocchi A et al. 2004;20:319–325. 18. Schnitzler L. Le´ sions urticariennes chro- Recommendations for assessing patient- 11. Nakamura Y, Kambe N, Saito M, Nishiko- niques permanentes (e´ rythe` me pe´ taloı¨ de?). J reported outcomes and health-related quality mori R, Kim YG, Murakami M et al. Mast Dermatol Angers 1972;Cas cliniques No 46 of life in clinical trials on allergy: a GA(2) cells mediate neutrophil recruitment and vas- B:Abstract 46. LEN taskforce position paper. Allergy cular leakage through the NLRP3 inflamma- 19. Lipsker D, Veran Y, Grunenberger F, Cribi- 2010;65:290–295. some in histamine-independent urticaria. J er B, Heid E, Grosshans E. The Schnitzler 3. Zuberbier T, Asero R, Bindslev-Jensen C, Exp Med 2009;206:1037–1046. syndrome. Four new cases and review of the Walter Canonica G, Church MK, Gimenez- 12. Goldbach-Mansky R, Dailey NJ, Canna literature. Medicine (Baltimore) 2001;80:37– Arnau AM et al. EAACI/GA(2)LEN/EDF/ SW, Gelabert A, Jones J, Rubin BI et al. 44. WAO guideline: management of urticaria. Neonatal-onset multisystem inflammatory 20. de Koning HD, Bodar EJ, van der Meer Allergy 2009;64:1427–1443. disease responsive to interleukin-1beta inhi- JW, Simon A. Schnitzler syndrome: beyond 4. Peroni A, Colato C, Zanoni G, Girolomoni bition. N Engl J Med 2006;355:581–592. the case reports: review and follow-up of 94 G. Urticarial lesions: if not urticaria, what 13. Hoffman HM, Throne ML, Amar NJ, Sebai patients with an emphasis on prognosis and else? The differential diagnosis of urticaria: M, Kivitz AJ, Kavanaugh A et al. Efficacy treatment. Semin Arthritis Rheum part II. Systemic diseases J Am Acad Derma- and safety of rilonacept (interleukin-1 Trap) 2007;37:137–148. tol 2010;62:557–570; quiz 571–572. in patients with cryopyrin-associated peri- 21. Lipsker D. The Schnitzler syndrome. Orpha- 5. Van der Hilst JC, Simon A, Drenth JP. odic syndromes: results from two sequential net J Rare Dis 2010;5:38. Hereditary periodic fever and reactive amy- placebo-controlled studies. Arthritis Rheum 22. Asli B, Brouet JC, Fermand JP. Spontane- loidosis. Clin Exp Med 2005;5:87–98. 2008;58:2443–2452. ous remission of Schnitzler syndrome. Ann 6. Stych B, Dobrovolny D. Familial cold auto- 14. Lachmann HJ, Kone-Paut I, Kuemmerle- Allergy Asthma Immunol 2011;107:87–88. inflammatory syndrome (FCAS): character- Deschner JB, Leslie KS, Hachulla E, Quar- 23. Pizzirani C, Falzoni S, Govoni M, La Corte ization of symptomatology and impact on tier P et al. Use of canakinumab in the R, Donadei S, Di Virgilio F et al. Dysfunc- patients’ lives. Curr Med Res Opin cryopyrin-associated periodic syndrome. N tional inflammasome in Schnitzler’s syn- 2008;24:1577–1582. Engl J Med 2009;360:2416–2425. drome. Rheumatology (Oxford) 7. van der Hilst JC, Bodar EJ, Barron KS, 15. Kuemmerle-Deschner JB, Hachulla E, Cart- 2009;48:1304–1308. Frenkel J, Drenth JP, van der Meer JW wright R, Hawkins PN, Tran TA, Bader- 24. Martinez-Taboada VM, Fontalba A, Blanco et al. Long-term follow-up, clinical features, Meunier B et al. Two-year results from an R, Fernandez-Luna JL. Successful treatment and quality of life in a series of 103 patients open-label, multicentre, phase III study eval- of refractory Schnitzler syndrome with ana- with hyperimmunoglobulinemia D syn- uating the safety and efficacy of cana- kinra: comment on the article by Hawkins et drome. Medicine (Baltimore) 2008;87:301– kinumab in patients with cryopyrin- al.. Arthritis Rheum 2005;52:2226–2227. 310. associated periodic syndrome across different 25. Schneider SW, Gaubitz M, Luger TA, Bons- 8. Aksentijevich I, C DP, Remmers EF, Muel- severity phenotypes. Ann Rheum Dis mann G. Prompt response of refractory ler JL, Le J, Kolodner RD et al. The clinical 2011;70:2095–2102. Schnitzler syndrome to treatment with ana- continuum of cryopyrinopathies: novel 16. Kuemmerle-Deschner JB, Tyrrell PN, Koet- kinra. J Am Acad Dermatol 2007;56(5 Sup- CIAS1 mutations in North American ter I, Wittkowski H, Bialkowski A, Tzariba- pl):S120–S122. patients and a new cryopyrin model. Arthri- chev N et al. Efficacy and safety of anakinra 26. Dybowski F, Sepp N, Bergerhausen HJ, tis Rheum 2007;56:1273–1285. therapy in pediatric and adult patients with Braun J. Successful use of anakinra to treat 9. Petrilli V, Dostert C, Muruve DA, Tschopp the autoinflammatory Muckle-Wells syn- refractory Schnitzler’s syndrome. Clin Exp J. The inflammasome: a danger sensing com- drome. Arthritis Rheum 2011;63:840–849. Rheumatol 2008;26:354–357.

27. de Koning HD, Schalkwijk J, van der Meer arthritis with active systemic features. Arthri- 47. Kallinich T, Wittkowski H, Keitzer R, Roth JW, Simon A. Successful canakinumab treat- tis Rheum 2012;64:557–567. J, Foell D. Neutrophil-derived S100A12 as ment identifies IL-1beta as a pivotal media- 38. Quartier P, Allantaz F, Cimaz R, Pillet P, novel biomarker of inflammation in familial tor in Schnitzler syndrome. J Allergy Clin Messiaen C, Bardin C et al. A multicentre, Mediterranean fever. Ann Rheum Dis Immunol 2011;128:1352–1354. randomised, double-blind, placebo-con- 2010;69:677–682. 28. Krause K, Weller K, Stefaniak R, Wittkow- trolled trial with the interleukin-1 receptor 48. Lachmann HJ, Goodman HJ, Gilbertson ski H, Altrichter S, Siebenhaar F et al. Effi- antagonist anakinra in patients with sys- JA, Gallimore JR, Sabin CA, Gillmore JD cacy and safety of the interleukin-1 temic-onset juvenile idiopathic arthritis et al. Natural history and outcome in sys- antagonist rilonacept in Schnitzler syndrome: (ANAJIS trial). Ann Rheum Dis 2011;70:747 temic AA amyloidosis. N Engl J Med an open-label study. Allergy 2012;67:943– –754. 2007;356:2361–2371. 950. 39. Yokota S, Imagawa T, Mori M, Miyamae 49. Lachmann HJ, Lowe P, Felix SD, Rordorf 29. Jeru I, Duquesnoy P, Fernandes-Alnemri T, T, Aihara Y, Takei S et al. Efficacy and C, Leslie K, Madhoo S et al. In vivo regula- Cochet E, Yu JW, Lackmy-Port-Lis M et al. safety of tocilizumab in patients with sys- tion of interleukin 1beta in patients with Mutations in NALP12 cause hereditary peri- temic-onset juvenile idiopathic arthritis: a cryopyrin-associated periodic syndromes. J odic fever syndromes. Proc Natl Acad Sci randomised, double-blind, placebo-con- Exp Med 2009;206:1029–1036. USA 2008;105:1614–1619. trolled, withdrawal phase III trial. Lancet 50. Aksentijevich I, Nowak M, Mallah M, Chae 30. Borghini S, Tassi S, Chiesa S, Caroli F, 2008;371:998–1006. JJ, Watford WT, Hofmann SR et al. De Carta S, Caorsi R et al. Clinical presentation 40. Frosch M, Roth J. New insights in systemic novo CIAS1 mutations, cytokine activation, and pathogenesis of cold-induced autoin- juvenile idiopathic arthritis–from pathophys- and evidence for genetic heterogeneity in flammatory disease in a family with recur- iology to treatment. Rheumatology (Oxford) patients with neonatal-onset multisystem rence of an NLRP12 mutation. Arthritis 2008;47:121–125. inflammatory disease (NOMID): a new Rheum 2011;63:830–839. 41. Stoffels M, Simon A. Hyper-IgD syndrome member of the expanding family of pyrin- 31. Yamaguchi M, Ohta A, Tsunematsu T, Ka- or mevalonate kinase deficiency. Curr Opin associated autoinflammatory diseases. Arthri- sukawa R, Mizushima Y, Kashiwagi H et al. Rheumatol 2011;23:419–423. tis Rheum 2002;46:3340–3348. Preliminary criteria for classification of adult 42. Rezaei N. TNF-receptor-associated periodic 51. Ait-Idir D, Khilan A, Djerdjouri B, El-Shan- Still’s disease. J Rheumatol 1992;19:424–430. syndrome (TRAPS): an autosomal dominant ti H. Spectrum of mutations and carrier fre- 32. Yamamoto T. Cutaneous manifestations multisystem disorder. Clin Rheumatol quency of familial Mediterranean fever gene associated with adult-onset Still’s disease: 2006;25:773–777. in the Algerian population. Rheumatology important diagnostic values. Rheumatol Int 43. Weller K, Viehmann K, Brautigam M, Kra- (Oxford) 2011;50:2306–2310. 2012;32:2233–2237. use K, Siebenhaar F, Zuberbier T et al. 52. Gattorno M, Sormani MP, D’Osualdo A, 33. Riera E, Olive A, Narvaez J, Holgado S, Cost-intensive, time-consuming, problemati- Pelagatti MA, Caroli F, Federici S et al. A Santo P, Mateo L et al. Adult onset Still’s cal? How physicians in private practice expe- diagnostic score for molecular analysis of disease: review of 41 cases. Clin Exp Rheu- rience the care of urticaria patients J Dtsch hereditary autoinflammatory syndromes with matol 2011;29:331–336. Dermatol Ges 2012;10:341–347. periodic fever in children. Arthritis Rheum 34. Efthimiou P, Kontzias A, Ward CM, Ogden 44. Kieffer C, Cribier B, Lipsker D. Neutrophil- 2008;58:1823–1832. NS. Adult-onset Still’s disease: can recent ic urticarial dermatosis: a variant of neutro- 53. Hoffman HM, Wanderer AA, Broide DH. advances in our understanding of its patho- philic urticaria strongly associated with Familial cold autoinflammatory syndrome: genesis lead to targeted therapy? Nat Clin systemic disease. Report of 9 new cases and phenotype and genotype of an autosomal Pract Rheumatol 2007;3:328–335. review of the literature. Medicine (Balti- dominant periodic fever. J Allergy Clin 35. Prakken B, Albani S, Martini A. Juvenile more) 2009;88:23–31. Immunol 2001;108:615–620. idiopathic arthritis. Lancet 2011;377:2138– 45. Krause K, Feist E, Fiene M, Kallinich T, 54. Gandhi C, Healy C, Wanderer AA, Hoff- 2149. Maurer M. Complete remission in 3 of 3 man HM. Familial atypical cold urticaria: 36. Nigrovic PA, Mannion M, Prince FH, Zeft anti-IL-6-treated patients with Schnitzler description of a new hereditary disease. J A, Rabinovich CE, van Rossum MA et al. syndrome. J Allergy Clin Immunol Allergy Clin Immunol 2009;124:1245–1250. Anakinra as first-line disease-modifying ther- 2012;129:848–850. 55. Wanderer AA, Hoffman HM. The spectrum apy in systemic juvenile idiopathic arthritis: 46. Vaitla PM, Radford PM, Tighe PJ, Powell of acquired and familial cold-induced urti- report of forty-six patients from an interna- RJ, McDermott EM, Todd I et al. Role of caria/urticaria-like syndromes. Immunol tional multicenter series. Arthritis Rheum interleukin-6 in a patient with tumor necro- Allergy Clin North Am 2004;24:259–286, vii. 2011;63:545–555. sis factor receptor-associated periodic syn- 56. Kivity S, Schwartz Y, Wolf R, Topilsky M. 37. Ruperto N, Quartier P, Wulffraat N, Woo drome: assessment of outcomes following Systemic cold-induced urticaria–clinical and P, Ravelli A, Mouy R et al. A phase II, treatment with the anti-interleukin-6 receptor laboratory characterization. J Allergy Clin multicenter, open-label study evaluating dos- monoclonal antibody tocilizumab. Arthritis Immunol 1990;85(1 Pt 1):52–54. ing and preliminary safety and efficacy of Rheum 2011;63:1151–1155. canakinumab in systemic juvenile idiopathic